IE891908L - Novel esters - Google Patents
Novel estersInfo
- Publication number
- IE891908L IE891908L IE891908A IE190889A IE891908L IE 891908 L IE891908 L IE 891908L IE 891908 A IE891908 A IE 891908A IE 190889 A IE190889 A IE 190889A IE 891908 L IE891908 L IE 891908L
- Authority
- IE
- Ireland
- Prior art keywords
- estramustlne
- aminoacetate
- methylaminoacetate
- mol
- compound
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/40—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings
- C07C271/42—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C271/46—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by halogen atoms or by nitro or nitroso groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
- C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
- C07J41/0072—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the A ring of the steroid being aromatic
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Steroid Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Plural Heterocyclic Compounds (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Cephalosporin Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The present invention concerns novel compounds having the general formula wherein R<1>, R<2> and R<3> are selected from the group consisting of hydrogen or lower alkyl having 1-4 carbon atoms, wherein R<2> and R<3> together with the N atom can also form a ring having 2-5 carbon atoms and wherein n is 0, 1 or 2, and pharmaceutically acceptable salts thereof. The compounds according to the invention are useful as anticancer agents.
Description
6 2 4 6 9 1 The present invention concerns novel esters having anticancer activity. Specifically the Invention concerns novel esters of « estramustlne.
Estramustlne, estra-l,3,5(l0)-tr1ene-3,l7y£-d1ol 3-/N,N-bis-» 5 (2-chloroethyl)carbamate/, and various esters thereof are previous ly known as antineoplastic agents from e.g. the US patent 3,299,104. One of these esters, 17-estramustlne dlhydrogen phosphate ester, or abbreviated EMP, has been further developed and water soluble salts thereof, EstracytR, are now widely used for 10 treating prostatic cancer. A problem with the water soluble salts of EMP when taken orally concerns the Interaction with calcium ions in food and drinks. In the presence of calcium 1ons these EMP salts give precipitates and form an Insoluble complex, which is not absorbed from the gastrointestinal tract and therefore has 15 very little activity 1n the body. Several attempts to overcome this problem have been made, both as regards the pharmaceutical preparation of EMP salts and of estramustlne as such. It has, however, not been possible to find EMP modifications for oral use, which 1n the presence of calcium ions produce the same plasma le-20 vels of the main EMP metabolites estramustine and the corresponding 17-keto compound, estromustlne, as does the water soluble disodium salt of EMP when taken 1n absence of calcium.
Unexpectedly 1t has now been found that the problem with the calcium Interaction can be avoided and that the plasma levels of 25 estramustlne and estromustlne as well as the anticancer activity can be maintained at an essentially unchanged or even higher level 1f the estramustlne 1s administered 1n the form of certain amino acid esters.
Amino acid esters for pharmaceutical purposes have been de-30 scribed In the British Patent 962,797 and 1n the European Patent Application 0104746. The alms of the Inventions of these appllca-f tlons, however, are different from the aim of the present invention and the alcohols esterlfied, although containing a steroid skeleton, have structures widely different from that of estramustlne. oc The present Invention concerns novel compounds having the 2 general formula: C1CH9CH9^ o c <■ \ II ^ N-C-0 C1CH2CH2' 0 R1 f H I / O-C-CH-(CH^) -N CH3j ^n3 wherein R1, R2 and R3 are selected from hydrogen and lower alkyl having 1-4 carbon atoms, wherein R2 and R3 together with the N 5 atom can form a ring having 2-5 carbon atoms, and wherein n 1s 0, 1 or 2, and pharmaceutically acceptable salts thereof. Preferred compounds are those where n=0, R* 1s hydrogen and R2 and R3 are equal or different and are hydrogen, methyl or ethyl.
The following compounds are especially preferred. 10 17-estramustlne N,N-diethyl aminoacetate 17-estramustlne 4-(N,N-d1methylam1no)butyrate 17-estramustine N-methylaminoacetate 17-estramustlne aminoacetate 17-estramusti ne 2-am1noproplonate 15 17-estramustine N-ethylaminoacetate 17-estramustine N-(2-propyl)am1noacetate 17-estramusti ne 3-ami nopropi onate 17-estramustine N-(l-propyl)am1noacetate The novel compounds are normally prepared from estramustlne 20 using conventional methods, two of them being mentioned below. The preparation of estramustlne Itself 1s disclosed 1n e.g. the US patent 3,299,104.
In one of the methods estramustlne 1s esterlfled with an acid containing a reactive substltuent such as halogen, e.g. chlo-25 ro, bromo, 1odo, or organic sulfonyloxy, organic being a hydrocarbon residue, containing 1 to 6 carbon atoms, giving an Intermediate having formula II, 3 cich2CH2n^ C1CH2CH2 N-C-0 0-C-CH-(.CH„) -R , I c n II where R4 is the reactive substltuent. The Intermediate 1s then reacted with amines HNR2R3 giving the novel compounds having formula I. 5 According to the other method estramustlne 1s esterlfled with an amino acid having the general formula H00C-£H-(CH2)n-NR2R5' wherein R5 1s R3 or optionally a protecting group, giving an Intermediate having the general formula II, wherein R4 1s -NR2R5, from which the protecting group 1s afterwards removed for the pre-10 paratlon of compounds having the general formula I. Examples of substltuents R5 protecting the amino group are t-butoxycarbonyl and benzyloxycarbonyl.
For the ester1f1cat1on well known methods are used. One type of method 1s based on reactions with reactive derivatives of 15 the adds such as acyl chlorides, bromides and mixed anhydrides with organic acids Including those obtained from lower alkyl chlo-roformates. Another type of method 1s based on reactions with adds 1n the presence of dehydrating agents, e.g. l,l-carbonyld1-1m1dazole and N,N'-d1cyclohexylcarbod11mide. 20 The salts of the novel compounds are prepared from the base- form of the compound and pharmaceutically accepted acids, e.g". those listed 1n International Journal of Pharmaceutics 3, 202 (1986), which 1s hereby Incorporated by reference. Preferred acids are hydrochloric add, hydrobromlc acid, methanesulfonic 25 acid and ethanesulfonlc add. 4 Among the salts of the novel compounds the following are specially preferred: 17-estramustine N-methylaminoacetate, hydrochloride; 17-estramustine aminoacetate, hydrochloride; 17-estramustlne N-methylaminoacetate, methanesulfonate; 17-estramustlne 5 aminoacetate, methanesulfonate; 17-estramustlne N-methylaminoacetate, ethanesulfonate and 17-estramustlne aminoacetate, ethanesulfonate.
Although the compounds according to the Invention are at first hand intended for oral use 1t 1s obvious that other ways of 10 administration are within the scope of the Invention.
Pharmaceutical formulations are thus usually prepared from a predetermined quantity of one or more of the compounds of the invention. Such formulations may take the form of powders, granules (pellets), suppositories, capsules or tablets, suspensions, etc. 15 with or without, but preferably with, any one of a large variety of pharmaceutically acceptable exclplents. When 1n a mixture with a pharmceutlcal vehicle or carrier, the active ingredient usually comprises from about 0.01 to 95 percent, normally from about 0.05 to about 80 percent, by weight of the composition. Carriers such 20 as cellulose, sugar, talc, commonly used synthetic and natural gums, natural and synthetic oils, emulsifying and dispersing agents, water, and the like, may be used 1n such formulations. Binders such as polyvinylpyrrolidone and lubricants such as magnesium stearate, may be used to form tablets. Disintegrating agents 25 such as starch may also be included 1n tablets.
The compositions are preferably formulated 1n a unit dosage form, each dosage containing from about 0.05 to about 1000 mg, more usually about 5 to about 300 mg of the active Ingredient. The term "unit dosage form" refers to physically discrete units 30 suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of the new ester calculated to produce the desired therapeutic effect, In association with the required pharmaceutical carrier.
The compound according to the invention 1s effective over a 35 wide dosage range. For example, dosages per day will normally fall within the range of about 0.1 to about 100 mg/kg of body weight. In the treatment of adult humans, the range of about 0.5 5 to about 50 mg/kg, 1n single or divided doses, 1s preferred. It will be understood that the amount of the compound actually administered will be determined by a physician, 1n the light of the relevant circumstances Including the condition to be treated, the 5 chosen route of amin1strati on, the age, weight, and response of the Individual patient, and the severity of the patient's symptoms, and therefore the above dosage ranges are not Intended to limit the scope of the Invention 1n any way. As used herein the terms "pharmaceutical compositions" and "pharmaceutically accep-10 table" Include compositions and Ingredients for both human and veterinary use.
The following examples are Intended to Illustrate but not to limit the scope of the invention, although the compounds named are of particular Interest for our Intended purposes. 15 Example 1 17-Estramustine chloroacetate Estramustlne (4.4 g, 0,01 mol) 1s dissolved 1n toluene (100 ml). Chloroacetyl chloride (1.7 g, 0.015 mol) 1s added and the solution 1s heated at 70°C for 1.5 hours. The solvent 1s then remo-20 ved in a rotary evaporator at 30°C. The residue 1s treated with ethanol (40 ml) and the product crystallizes. The product 1s collected on a filter and washed with a few ml of ethanol. The chloroacetate after drying at room temperature melts at 95°C. Yield 4.9 g. 25 Example 2 17-Estramustine bromoacetate This compound 1s prepared by a method similar to the one described 1n example 1 from estramustlne and bromoacetyl bromide. M.p. 109°C. 30 Example 3 17-Estramust1ne N-methylaminoacetate, hydrochloride 17-Estramustine chloroacetate (5.2 g, 0.01 mol) 1s dissolved 1n acetonltrlle (40 ml) at room temperature. Methylamlne (3.1. g) (0.1 mol) dissolved 1n cold acetonltrlle (10 ml) at 0°C 1s added. 35 After 3 h the excess of amine and the solvent 1s removed 1n a rotary evaporator. The residue 1s dissolved 1n methylene chloride (50 ml) and washed three times with 50 ml water, pH being adjusted 6 each time to 7-9 with a sodium bicarbonate solution. The methylene chloride solution 1s dried over anhydrous sodium sulfate and the solvent 1s carefully evaporated. The residue 1s dissolved 1n acetonltrlle (40 ml) and the N-methylaminoacetate ester 1s precl-5 pltated by the addition of a solution of hydrogen chloride 1n ether (0.012 mol). A voluminous precipitate 1s formed which after stirring for a few minutes disintegrates to fine crystals. The product 1s collected on a filter and washed with a mixture of ethylacetate and acetonltrlle (1:1). The hydrochloride 1s then 10 dried under vacuum at room temperature for 24 h. Yield 3.7 g. M.p. 226°C, with decomposition. NMR spectroscopy shows that the structure of the product 1s estramustlne 17-N-methylaminoacetate.
Example 4 17-Estramust1ne N-methylaminoacetate, methanesulfonate and ethane-15 sulfonate Using the method described 1n example 3 except for using a solution of methanesulfonlc acid or ethanesulfonic add 1n ether Instead of hydrogen chloride 1n ether a methanesulfonate, m.p. 212°C, or an ethanesulfonate, m.p. 170°C, respectively, are obtaln-20 ed (compounds Nos. 4:1 and 4:2, respectively).
Example 5 17-Estramust1ne N-R2-N-R3-am1noacetate. hydrochloride Esters having the amino substltuents R2 and R3 described 1n table 1 are made from 17-estramustlne bromoacetate using the method 25 of example 3 with minor modifications.
Table 1 R2 R3 Hydrochlorlde m.p. °c Amine used -ch3 -ch3 210 (ch3)2nh H -ch2ch3 220 ch3ch2nh2 H -ch2ch2ch3 170 ch3ch2ch2nh2 H -ch(ch3)2 200 (ch3)2chnh2 H -c(ch3)3 172 (ch3)3cnh2 -ch2ch3 -ch2ch3 158 (ch3ch2)2nh -ch2-ch2- ch2-ch2- 210 nh 7 Example 6 17-Estramust1ne aminoacetate, hydrochloride and methanesulfonate Estramustlne (4.4 g, 0.01 mol) and N-tert-butoxycarbonyl-glycine (1.75 g, 0.01 mol) are dissolved 1n methylene chloride (35 5 ml). D1cyclohexy1carbod11m1de (2.1 g, 0.01 mol) and 4-d1methyl-aminopyrldlne (0.1 g, 0,001 mol) are added and the reaction mixture 1s stirred for 3 hours. The dlcyclohexylurea formed 1s removed by filtration and the solvent 1s carefully evaporated. The oily residue 1s dissolved 1n acetonltrlle (10 ml). Acetonltrlle (40 ml) 10 containing hydrogen chloride (0.03 mol) 1s added and the mixture is stirred for 16 hours. The precipitate formed 1s collected on a filter and recrystalllzed from methanol/ether. Yield 3.2 g of 17-estramustlne aminoacetate, hydrochloride, (m.p. 220°C, compound No. 6:1) as confirmed by NMR-spectro-scopy. 15 With the same method except for using methanesulfonlc acid (0.03 mol) Instead of hydrogen chloride and omitting the recrys-talllzation 17-estramustine aminoacetate, methanesulfonate (compound No. 6:2) 1s obtained, m.p. 206°C.
Example 7 20 17-Estramust1ne amlnopropionates, hydrochlorides Using the method described In example 6 the following salts are obtained: 17-estramustlne 2-L-aminoprop1onate, hydrochloride, m.p. 248°C, from N-tert-butoxycarbony1-L-alan1ne 25 17-estramustine 3-am1noprop1onate, hydrochloride, m.p. 223°C, from N-tert-butoxycarbony1-y8 -alan1ne Example 8 17-Estramust1ne aminoacetate, methanesulfonate To estramustlne (4.4 g, 0.01 mol) dissolved 1n methylene 30 chloride (30 ml) Is added N-benzyloxycarbonylglycine (2.2 g, 0.01 mol), d1cyclohexylcarbod11m1de (2.25 g, 0,011 mol) and 4-d1methylam1no-pyr1d1ne (0.12 g, 0.001 mol). The mixture 1s stirred at room temperature for 2 h. The dlcyclohexylurea formed 1s removed by filtration. The filtrate 1s washed with hydrochlo-35 rlc acid (2 mol/1, 10 ml), water (10 ml), sodium carbonate solution (1 mol/1, 25 ml) and with water (25 ml) and dried with sodium sulfate. The solvent is evaporated 1n a rotary evaporator. The residual oil 1s dissolved 1n ethanol (125 ml). 8 Palladium on carbon (1 g, Pd-content 5%) 1s added and the mixture 1s treated with hydrogen at atmospheric pressure and room temperature. When the reaction has ceased the mixture 1s filtered and the solvent 1s evaporated carefully. The residue 1s dissolved 1n ace-5 tonltrlle (75 ml). Methanesulfonlc acid (1 g, 0.01 mol) 1s added.
After stirring of the mixture for 18 h the precipitate 1s collected on a filter and washed with acetonltrlle and dried at room temperature. Yield 3.7 g of 17-estramustlne aminoacetate, methanesulfonate, m.p. 204°C. 10 Example 9 17-Estramust1ne 4-(N,N-d1methylatn1no)butyrate, hydrochloride To estramustlne (4.4 g, 0,01 mol) In methylene chloride (50 ml) 1s added 4-d1methylaminobutyry1 chloride, hydrochloride, (1,3 g, 0.01 mol). The solution 1s refluxed for 2 h. The solvent 1s 15 evaporated and the resulting oil crystallizes. The product 1s treated with activated carbon 1n ethanol solution and recrystalUz-ed from ethanol/ether. Yield 6.5 g. M.p. 205°C. The product 1s 17-estramustlne 4-(N,N-d1-methylam1no)butyrate, hydrochloride, as confirmed by NMR-spectroscopy. 20 Example 10 Interactions with calcium 1ons Solution A: 0.3 mole/1 calcium dlethanesulfonate. Calcium carbonate (1.38 g, 15 mmole) 1s dissolved by adding a 1.0 mole/1 ethanesulfonic acid solution until a stable pH-5.3 1s obtained. The 25 solution 1s diluted with water to 50 ml.
Solution B: 0.03 mole/1 calcium dlethanesulfonate. One part of solution A 1s diluted with 9 parts of water.
Solution C: 0.05 mole/1 sodium acetate/acetic add buffer with pH= 4.5. Glacial acetic acid (3.0 g, 0.05 mole) 1s dissolved 1n 800 30 ml of water, titrated with 1 mole/1 sodium hydroxide solution to pH=4.5 and diluted to 1 1.
The test compound 1s dissolved 1n 50 ml of solution C. A clear solution 1s obtained 1n a few minutes. After 5 minutes an equlmolar amount of calcium 1ons are added by adding 1 ml of solute tlon A or B. The mixture 1s observed for 3 h. 9 5 10 TEST COM POUND Solution added, mmole calcium 1ons Observation Amount mg mmole Estramustlne phosphate, 16 0.03 B, 0.03 Becomes unclear dlsodlum salt Immediately Compound No. 6:2 178 0.3 A, 0.3 Remains clear " 4:2 186 0.3 A, 0.3 N U The results show that the novel compounds 1n the presence of calcium 1ons do not give any precipitate at concentrations 10 times higher than the concentrations of estramustlne phosphate di-sodlum salt and calcium 1ons required to give an Immediate 15 formation of an undissolved estramustlne phosphate calcium salt. Example 11 Comparison of estramustlne phosphate and novel estramustlne esters with respect to oral bioavailability of estramustlne in dogs Different formulations were administered orally to groups of 20 four Beagle dogs. The dose was equivalent to 140 mg of estramustlne phosphate. The animals were fasting before dosing and given 50 ml 0.01 M hydrochloric acid after the dose. Blood samples were analysed for estramustlne by means of gas chromatography. (Andersson, S-B, et al., Acta Pharm.Suec. 19, 1 (1982). 25 The following formulations were used: 1. Water solution of estramustlne phosphate dlsodlum salt 2. Water solution of compound No. 6:2 3. Water solution of compound No. 4:2 Table 1 shows the areas under the plasma concentration "ver-30 sus time curves, AUC, of estramustlne 1n dogs. The mean values were 54 + 62, 118 + 60 and 83 + 62 ng/mlxhours for estramustine phosphate, compound No. 6:2 and No. 4:2, respectively. 10 TABLE 1 Oral bioavailability of estramustlne 1n dogs. AUC-values after administration of solutions of the estramustlne esters Dog No. Estramustlne 5 phosphate Compound No. 6:2 Compound No. 4:2 dlsodlum salt 8727 147 100 8729 16.4 140 94.0 8731 34.0 45.8 79.8 10 8733 19.5 184.8 8735 - - 2.6 8742 - - 153.4 Mean±S.D. 54.3 i 62.4 118 t 59 82.6 t 62.0 15 Example 12 Formulation, plain tablets I Compound No. 6:2, mg 160 Corn starch, mg 15 II Polyvldone, mg 8 Ethanol q.s.
III Corn starch, mg 15 Magnesium stearate, mg 2 I 1s mixed and granulated with solution II. After drying and milling through 1 mm sieve III 1s added. The mixture 1s compressed to tablets with a weight of 200 mg.
Example 13 Formulation, capsules The mixture from example 12 1s filled into hard capsules, size No. 1. 11
Claims (1)
1. CLAIMS Novel compounds having the general formula 0-C-CH-(CH 0 R I! I C1CH-CH 2 2 * wherein R1, R2 and R3 are selected from the group consisting of hydrogen or lower alkyl having 1-4 carbon atoms, wherein R2 and R3 together with the N atom can also form a ring having 2-5 carbon atoms and wherein n 1s 0, 1 or 2, and pharmaceutically acceptable salts thereof. Compounds according to claim 1 characterized 1n that n Is 0. Compounds according to claim 1 or 2 characterized In that R1 1s hydrogen. Compounds according to any of the claims 1-3, characterized 1n that R2 and R3 are equal or different and consist of hydrogen, methyl or ethyl. A compound according to claim 1 selected from the following group: 17-estramustlne N(N-d1ethylam1noacetate 17-estramustlne 4-(N,N-d1methy1am1no)butyrate 17-estramustlne N-methylaminoacetate 17-estramustlne aminoacetate 17-estramustlne 2-am1noprop1onate 17-estramustine N-ethy1aminoacetate 17-estramustlne N-(2-propyl)am1noacetate 17-estramustlne 3-am1 noprop1onate 17-estramustlne N-(l-propyl)aminoacetate 12 A compound according to claim 1 selected from the following group: 17-estramustlne N-methylaminoacetate, hydrochloride 17-estramustlne aminoacetate, hydrochloride 17-estramustlne N-methylaminoacetate, methanesulfonate 17-estramustlne aminoacetate, methanesulfonate 17-estramustlne N-methylaminoacetate, ethanesulfonate 17-estramustlne aminoacetate, ethanesulfonate 10 Method of preparing compounds having the general formula I characterized by a) estrlfylng estramustlne with an acid having a reactive subs-tltuent giving a compound having the formula II: ClCHjCHj' | ^ | C1CH2CH2
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE8802402A SE8802402D0 (en) | 1988-06-28 | 1988-06-28 | NOVEL ESTERS |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE891908L true IE891908L (en) | 1989-12-28 |
| IE62462B1 IE62462B1 (en) | 1995-02-08 |
Family
ID=20372746
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE190889A IE62462B1 (en) | 1988-06-28 | 1989-06-13 | Novel esters of estramustine |
Country Status (25)
| Country | Link |
|---|---|
| US (1) | US5036062A (en) |
| EP (1) | EP0351561B1 (en) |
| JP (1) | JP2563587B2 (en) |
| KR (1) | KR910000607A (en) |
| CN (1) | CN1031060C (en) |
| AT (1) | ATE96446T1 (en) |
| CA (1) | CA1317587C (en) |
| DD (1) | DD284026A5 (en) |
| DE (1) | DE68910211T2 (en) |
| DK (1) | DK318989A (en) |
| ES (1) | ES2059626T3 (en) |
| FI (1) | FI92707C (en) |
| HU (1) | HU203766B (en) |
| IE (1) | IE62462B1 (en) |
| IL (1) | IL90724A0 (en) |
| LT (1) | LT3548B (en) |
| LV (1) | LV10235B (en) |
| MD (1) | MD940402A (en) |
| NO (1) | NO172939C (en) |
| NZ (1) | NZ229649A (en) |
| PH (1) | PH30437A (en) |
| PT (1) | PT90986B (en) |
| RU (1) | RU2036929C1 (en) |
| SE (1) | SE8802402D0 (en) |
| ZA (1) | ZA894716B (en) |
Families Citing this family (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5124154A (en) * | 1990-06-12 | 1992-06-23 | Insite Vision Incorporated | Aminosteroids for ophthalmic use |
| US5209926A (en) * | 1990-06-12 | 1993-05-11 | Insite Vision Incorporated | Aminosteroids for ophthalmic use |
| US5252319A (en) * | 1990-06-12 | 1993-10-12 | Insite Vision Incorporated | Aminosteroids for ophthalmic use |
| US5256408A (en) * | 1990-06-12 | 1993-10-26 | Insite Vision Incorporated | Aminosteroids for ophthalmic use |
| JP2520074B2 (en) * | 1992-06-11 | 1996-07-31 | 呉羽化学工業株式会社 | Novel estradiol derivative-chlorambucil conjugate, method for producing the same, and pharmaceutical preparation |
| JPH07101977A (en) * | 1993-10-05 | 1995-04-18 | Kureha Chem Ind Co Ltd | New estradiol derivative with reduced hormone action and growth factor inhibitor thereof |
| FR2717690B1 (en) * | 1994-03-24 | 1996-04-26 | Roussel Uclaf | Application of aromatic steroids 3 substituted by an aminoalkoxy substituted for obtaining a medicament for controlling sterility, especially male sterility. |
| GB9419153D0 (en) * | 1994-09-22 | 1994-11-09 | Erba Carlo Spa | Estramustine formulations with improved pharmaceutical properties |
| US20030108764A1 (en) * | 2001-12-04 | 2003-06-12 | Neill John Thomas | Method for improving bonding of circuit board substrates to metal surfaces and the articles formed thereby |
| CN101463295B (en) * | 2008-11-28 | 2011-08-17 | 江苏海迅实业集团股份有限公司 | Cleaning agent for semiconductor industry |
| US9745338B2 (en) | 2013-07-11 | 2017-08-29 | Evestra, Inc. | Pro-drug forming compounds |
| WO2019078983A1 (en) | 2017-10-19 | 2019-04-25 | Evestra, Inc. | Longer-acting progestin prodrug contraceptives |
| CN112979744B (en) * | 2021-02-18 | 2022-02-15 | 齐齐哈尔医学院 | Diosgenin combined nitrogen mustard derivative with antitumor activity and preparation method and use thereof |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1126386B (en) * | 1959-11-14 | 1962-03-29 | Hoechst Ag | Process for the preparation of steroid 21-amino acid esters |
| US3299104A (en) * | 1963-04-09 | 1967-01-17 | Leo Ab | Certain steroid nu-bis-(haloethyl)-carbamates |
| US4443440A (en) * | 1982-08-30 | 1984-04-17 | The Upjohn Company | Amine containing ester prodrugs of corticosteroids |
| US4615835A (en) * | 1983-11-17 | 1986-10-07 | Stiftung Deutsches Krebsforschungs Zentrum | Steroid esters of N-(2-halogenethyl)-N-nitroso-carbamoylamino and acids and peptides therefore, as well as method for preparing them |
| JPS617292A (en) * | 1984-06-20 | 1986-01-13 | Japan Atom Energy Res Inst | Method for producing an estracytic compound bound to an anticancer drug |
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1988
- 1988-06-28 SE SE8802402A patent/SE8802402D0/en unknown
-
1989
- 1989-06-13 IE IE190889A patent/IE62462B1/en not_active IP Right Cessation
- 1989-06-13 US US07/365,436 patent/US5036062A/en not_active Expired - Fee Related
- 1989-06-16 CA CA000603014A patent/CA1317587C/en not_active Expired - Fee Related
- 1989-06-19 AT AT89111062T patent/ATE96446T1/en not_active IP Right Cessation
- 1989-06-19 ES ES89111062T patent/ES2059626T3/en not_active Expired - Lifetime
- 1989-06-19 DE DE89111062T patent/DE68910211T2/en not_active Expired - Fee Related
- 1989-06-19 EP EP89111062A patent/EP0351561B1/en not_active Expired - Lifetime
- 1989-06-21 ZA ZA894716A patent/ZA894716B/en unknown
- 1989-06-21 NZ NZ229649A patent/NZ229649A/en unknown
- 1989-06-23 IL IL90724A patent/IL90724A0/en not_active IP Right Cessation
- 1989-06-27 DK DK318989A patent/DK318989A/en not_active Application Discontinuation
- 1989-06-27 RU SU894614513A patent/RU2036929C1/en active
- 1989-06-27 CN CN89104490A patent/CN1031060C/en not_active Expired - Fee Related
- 1989-06-27 JP JP1162850A patent/JP2563587B2/en not_active Expired - Lifetime
- 1989-06-27 NO NO892672A patent/NO172939C/en unknown
- 1989-06-27 PH PH38864A patent/PH30437A/en unknown
- 1989-06-27 FI FI893130A patent/FI92707C/en not_active IP Right Cessation
- 1989-06-27 PT PT90986A patent/PT90986B/en not_active IP Right Cessation
- 1989-06-27 HU HU893235A patent/HU203766B/en not_active IP Right Cessation
- 1989-06-27 DD DD89330011A patent/DD284026A5/en not_active IP Right Cessation
- 1989-06-28 KR KR1019890009004A patent/KR910000607A/en not_active Abandoned
-
1993
- 1993-06-02 LT LTIP603A patent/LT3548B/en not_active IP Right Cessation
- 1993-06-08 LV LVP-93-514A patent/LV10235B/en unknown
-
1994
- 1994-07-14 MD MD94-0402A patent/MD940402A/en unknown
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MM4A | Patent lapsed |